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The More POR, The Better
Alumnus Goldstein Calls for More Clinical Research

By Rich McManus

On the Front Page...
There's not much difference between smart, sympatico collaboration among clinicians and bench scientists -- who love nothing more than sharpening their wits on patient histories and data -- and the clever concoctions of lyricists and musicians who craft a hit Broadway musical. Both thrive on the rebound and ricochet of sharp ideas and a hothouse atmosphere that both adds momentum to ideas that fly, and soundly trounces notions that are half-baked.

So stated Nobel laureate Dr. Joseph Goldstein, a former clinical associate at NHLBI who gave the first James A. Shannon Lecture on Jan. 13 before a packed house at Masur Auditorium. Goldstein -- now a professor and department chair at the medical school (University of Texas Southwestern Medical Center) from which he earned his M.D. -- erected his argument that "there has never been a better time for M.D.s to do clinical research" upon the formidable foundation of Shannon's career; the former NIH director (1955-1968) is credited with shaping much of the modern NIH and was himself an ardent clinician as well as bench scientist.

In a genial Southern twang that broadened words like type to "tap," Goldstein said most of the useful insights of medicine's past half century have been the result of collaborations between creative, alert physicians ("Those folks who actually see the patient, say hello and shake their hand," he quipped) and their allies at the bench who were able to sort through evidence to test daring hypotheses. His exemplars of "clinical investigation at its very best" were fellow Nobel laureates (1950) Philip Hench and Edward Kendall, a physician and Ph.D., respectively, who waded through a variety of clues to discover the steroid cortisone as a therapy for arthritis.

"The collaboration between a chemist, a clinician and a pharmaceutical company (in this instance Merck, which slogged through a 30-step chemical synthesis -- the most laborious of its kind up to then -- to make small quantities of cortisone) is like a good collaboration between partners writing a hit Broadway musical," he said. "Together, they produce a successful performance."

Indeed, Goldstein borrowed the title of his talk -- "The Clinical Investigator: Bewitched, Bothered and Bedeviled" -- from a similar line in Rodgers and Hart's Broadway hit Pal Joey.

Surveying the current state of medicine, with its emphasis on managed care and cost-cutting (which has led to "PAIDS" -- paralyzing academic investigator disease syndrome), Goldstein observes three categories of pursuit: pure basic research, disease-oriented research, and patient-oriented research. Although he gave historical examples of titans from each of these groups, his heart clearly is with the latter. His own career as an NHLBI clinical associate in Dr. Marshall Nirenberg's lab took off when the case of a youngster with hypercholesterolemia, to whom he was introduced by former NIH director Dr. Donald Fredrickson, began to consume him. Together with Dr. Michael S. Brown, then a young clinician in the arthritis institute, Goldstein began studies of cholesterol metabolism that won him and Brown a Nobel Prize in 1985.

Goldstein meets with fellow Nobelist and mentor Dr. Marshall Nirenberg, in whose lab Goldstein worked as an NHLBI clinical associate.

"NIH played a major role in our careers," said Goldstein, whose collaboration with Brown is now in its 25th year. Allowing that their work "has gotten more and more basic over the years," Goldstein nonetheless credits his clinical experience with engendering much of the pleasure he has obviously taken in his career.

Patient-oriented research, or POR, may get short shrift these days as scientists in general "are more interested in presenting their results at Cold Spring Harbor than at the Washington Sheraton," he jibed, but it tends to attract "fiercely independent people who avoid 'bandwagon' research at all costs." He described "the four P's of POR" -- passion, patients, patience and poverty." This last characteristic is where NIH may have a remedy, he suggested. "NIH could help by supporting more clinical research, work that is nonbandwagon and creative. Career development awards are needed."

Goldstein referred to bandwagon science as pernicious and "hard to stop once it gets started." Work in his own field involving genetic susceptibility to heart attacks has burgeoned with tiny advances, he said. Almost 900 papers describing variations in genes influencing plasma lipoproteins and their correlation with heart attacks appeared in the last decade. "But very little of it was useful, and it resulted in no new therapies or insights."

Fields that might attract bold mavericks today include gene therapy, epidemiology and chemo/cytokines, he said, adding optimistically that two papers published within a day of each other last August on bone morphogenetic proteins may result in some good to actual people some day.

Medicine's goal ought to be therapies, a drug, say, that can help a patient, but that is the hardest commodity to come by. This is an age, he showed, when one new gene is characterized, on average, each day, and one new biotech company opens each week, but only one new drug comes to market each year.

"What is needed is more patient-oriented research, and more patients," he stated. His prescription for the problem was Shannonesque: a creative environment such as Shannon created in Bldg. 3 when his hawkeyed recruitment garnered two eventual Nobelists, and 20 future members of the National Academy of Sciences; more NIH support for clinical research; and research partnerships, which he termed "absolutely crucial. These need to be collaborations among equals," not serfs doing the bidding of some research wizard, he emphasized.

Returning to the virtues of his career-long work with Brown, he said such partnerships "don't work without constant dialogue. You get into the habit of thinking out loud." He said the "embarrassment of sharing one another's lunacy" is far preferable to harboring crazy notions in the prison of one's skull. Another advantage to group work is that "you get rid of false ideas rapidly. Good collaboration stops nonsense."

Patient-oriented research "can be a great story with all the drama and excitement of a Broadway musical," he concluded. "The greatest commandments are to be original, avoid the bandwagon, and march to the beat of a different drummer."

NIH is starting to get in tune with the beat by hosting Clinical Research Day (see sidebar) at the Clinical Center on Feb. 10, said Dr. Michael Gottesman, NIH deputy director for intramural research.

The Shannon Lecture, one of a half dozen or so named lectureships at NIH, was established by the NIH Alumni Association to emphasize discussion of science and public policy. At the conclusion of his talk, Goldstein accepted a plaque from NIHAA marking the occasion.

Spotlight on Clinical Research

Clinical research will be in the spotlight on Feb. 10 when NIH sponsors its first Clinical Research Day. All sessions will be at the Clinical Center.

This event will celebrate the history of clinical research at NIH and, more importantly, the future of clinical research here," said Dr. John I. Gallin, CC director. He, Dr. Michael Gottesman, NIH deputy director for intramural research, and Dr. H. Clifford Lane, director of NIAID's Office of Clinical Research and head of the Clinical Research Special Interest Group, are program coordinators.

NIH director Dr. Harold Varmus will present the welcome at 9 a.m. in Masur Auditorium. He will also talk about the future of clinical research at noon.

The program kicks off with an overview by Gallin on CC revitalization. The design of what will be known as the Mark O. Hatfield Clinical Research Center will be covered by Robert J. Frasca of Zimmer Gunsul Frasca Partnership, the architectural firm designing the new building.

Dr. Alan Rabson, NCI deputy director, will present a look back at NIH clinical research in his presentation on moments of discovery.

Morning scientific presentations will cover brain imaging; obsessive-compulsive disorders in children; new treatments in sickle cell anemia; osteogenesis imperfecta; IL-2 therapy in AIDS; renal cell carcinoma; and hepatitis C and G.

Poster sessions will occupy the lunch break. Workshops are set for the afternoon. Offered concurrently at 2 p.m. are sessions on the future of diagnostics and the immune system. Planned for 3 p.m. are presentations on gene transfer and the nervous system.

Sessions will be in Masur Auditorium and Lipsett Amphitheater. No preregistration is required. Call 6-8025 for more information.

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